There is great need for new and less toxic treatments for human tropical diseases caused by parasitic kinetoplastids including trypanosomes (African sleeping sickness and Chagas' disease (American trypanosomiasis)) and leishmanias (oriental sore and kala-azar). In the case of Chagas' disease which is caused by Trypanosoma cruzi, there is currently no generally effective chemotherapy for the millions of people infected.
Among parasitic diseases, Trypanosoma cruzi infection is particularly difficult to treat by chemotherapy. At present the only drugs which are clinically available to treat Chagas' disease are nitroaromatic derivatives, but the well-documented host toxicity associated with such compounds has severely limited their application. While it has been apparent for some years that the antiparasitic action of nitroaromatic drugs involves reduction of the nitro function by parasite enzymes, attempts to improve the therapeutic index of these compounds have proceeded slowly on an ad hoc basis as the parasite enzymes responsible for nitro-reduction have not been identified. It has been found that the unique kinetoplastid enzyme, trypanothione disulfide reductase, can catalyze redox-cycling activity.
All pathogenic species of Kinetoplastida which have been examined are found to possess trypanothione and the enzyme, trypanothione disulfide reductase, which maintains a high intracellular concentration of this compound in the reduced (dithiol) form. As trypanothione reductase is ubiquitously distributed in Kinetoplastida and has no direct mammalian counterpart, it therefore represents an extremely important target for chemotherapy. The mammalian equivalent of trypanothione reductase is the enzyme glutathione disulfide reductase. Previous attempts to interrupt the activity of enzymes of this class have been based up on alkylating or acylating agents, but such approaches have, so far, met with little practical success. A need therefore exists for a therapeutic protocol and corresponding pharmaceutically effective compositions which will exhibit the requisite specificity and safety to successfully subvert the purpose of the anti-oxidant enzyme trypanothione reductase.